Diagnosis Of Neurofibromatosis Type Research Articles

FUNCTIONAL ANALYSIS OF AN NF1 SPLICING MUTATION THAT CAUSED EXON SKIPPING AND LED TO A TRUNCATED PROTEIN IN NEUROFIBROMATOSIS TYPE 1

Objective: Neurofibromatosis type 1 (NF-1) is caused by mutations in the NF1 gene that encodes neurofibromin, a negative regulator of RAS proto-oncogene. Approximately one-third of the reported pathogenic mutations in NF1 are splicing mutations, suggesting that splicing mutations are not rare. The objective of this study was to identify the pathogenicity of splicing mutation in a Chinese family with NF-1 and determine the effects of the pre-mRNA splicing mutation by in vitro functional analysis. Design and method: Next-generation sequencing was used to screen candidate mutations and Sanger sequencing was performed for validation. We performed a minigene splicing assay to determine the effect of the splicing mutation on NF1 expression and three-dimensional structure models of wild-type and mutant-type neurofibromin were generated using SWISS-MODEL and PROCHECK method, respectively. Results: Next-generation sequencing analysis identified a pathogenic splicing mutation c.479 + 1G>C in NF1 in the proband who had typical pigmental lesions and severe renal artery hypertension. We speculated that the causative mutation originated from the proband's mother who died of glioma. The minigene splicing assay showed that the c.479 + 1G>C mutation caused the skipping of exon 4, leading to a Glutamine to Valine substitution at position 97 in neurofibromin and an open reading frame shift terminating at codon 108. Three-dimensional modelling of neurofibromin showed that several major domains were missing in the truncated protein, which would have affected its function. Conclusions: The splicing mutation c.479 + 1G>C identified in a Chinese pedigree with NF-1 caused the skipping of exon 4 and resulted in a truncated protein. Our findings would be of great significance for the molecular diagnosis and management of NF-1 and showed that the minigene splicing assay is a powerful tool for analyzing mRNA expression outcomes caused by donor splicing site variation.

Is neurofibromatosis type 1 diagnosed in every patient who presents with café au lait macules? A single-center experience

Objective: Neurofibromatosis type 1 (NF1) is the most common hereditary neurocutaneous syndrome. The most crucial morbidity of
 NF1 is tumors that may develop. Cases with café-au-lait macules (CALMs) which is the first clinical finding of NF1, due to the anxiety
 of its associated morbidity, are referred to the pediatric oncology clinic. In this study, we aimed to examine the characteristics of the
 patients who applied to our outpatient clinic with CALMs.
 Patients and Methods: The data of 157 pediatric patients who applied to our institution with the diagnosis of CALMs between June
 2010 and November 2020 were analyzed retrospectively.
 Results: There were 157 pediatric cases referred to us for CALMs. According to the National Institutes of Health (NIH) diagnostic
 criteria, 109 (69.4%) cases were diagnosed with NF1. The diagnosis of 22 cases with NF1 were supported by genetic examination.
 Optic glioma was detected in 39 (24.8%) cases. In 15 (38.4%) of cases with optic glioma, visual functions were also affected. Second
 diagnostic criterion did not develop during the follow-up period, except for macules, in 48 cases (30.5%).
 Conclusion: In cases with multiple CALMs, the probability of NF1 diagnosis is high, and close and regular follow-up is of great
 importance in catching the development of the second clinical criterion and minimizing its morbidity.

Selumetinib (Koselugo)


 CADTH recommends that Koselugo be reimbursed by public drug plans for the treatment of pediatric patients aged 2 years and above, with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PNs), if certain conditions are met.
 Koselugo should only be covered to treat patients who are aged between 2 and 18 years with a diagnosis of NF1 with PNs that are causing symptoms and cannot be completely removed by surgery.
 Koselugo should only be reimbursed if prescribed by specialists with experience in managing NF1 and PNs, and the cost of Koselugo is reduced. To continue treatment with Koselugo longer than 18 months, the treating physician must provide proof that the patient is responding to treatment, including but not limited to reductions in symptoms of pain, improved motor function, and/or stabilization of disease, or proof of shrinking of tumours.

175P Breast cancer in neurofibromatosis type 1: A retrospective review in the Portuguese population

Neurofibromatosis type 1 (NF1) is a condition predisposing to the development of benign and malignant tumors. Regarding breast cancer, an increased risk has not been widely recognized or accepted. Given the oncogenic potential, long-term surveillance is important. We selected from a pool of 468 pts with NF1 from a site of reference in Portugal women >18 years and observed how they were screened for breast cancers (BC). Also, we evaluated the percentage of those who developed BC in our population, discussing the clinical evidence of increased BC risk in women with NF1 and the potential need for a high-risk screening protocol. We identified 179 women with NF1, 19 cases being excluded due to missing data. 114pts (71%) with confirmation of diagnosis NF1, the majority with familial history and 47% with spontaneous mutation. 17 with mutations identified, c.17657C>G, p (His553Asp) being the most prevalent (2 pts). 67% were under the age 50 years (y) at the time of data analysis. The median age was 43y (15-82) and at diagnosis of NF1 was 26 (1-62). For women <30y, only 2 pts started breast screening, due to breast alterations on breast palpation. No tumor was found. Above that, 92 pts were screened, mammography and breast ultrasound (71 pts) were the most required exam, followed by breast magnetic resonance imaging (MRI) (18pts) and with both (3pts). The periodicity was not sustained, with the time between exams being variable (annual to 3/3y). Medium BI-RADS 2, but 13 pts with BI-RADS 3. 23 patients without any screening tests beside all body MRI. There were 17 cases of BC in the follow-up period, however, twelve occurred in women in their 40s (median age 43y at diagnosis); 73% were < 50. The majority of the population presented with a grade 2 tumour, with hormone-receptor-positive BC (10), followed by HER2 amplification (4) and TNBC (1). Also, 2pts had two BC during the follow-up. However, we observe an early stage BC (I-II), with only 2 patients progressing to first-line treatment, being the only deaths observed in our population. Proposals for NF1 care and its specific manifestations have been developed but lack integration within routine care. This study reinforces that increased attention to the breast cancer risk in young women with NF1 is needed.

Functional Assays Combined with Pre-mRNA-Splicing Analysis Improve Variant Classification and Diagnostics for Individuals with Neurofibromatosis Type 1 and Legius Syndrome

Neurofibromatosis type 1 (NF1) and Legius syndrome (LS) are caused by inactivating variants in NF1 and SPRED1. NF1 encodes neurofibromin (NF), a GTPase-activating protein (GAP) for RAS that interacts with the SPRED1 product, Sprouty-related protein with an EVH (Ena/Vasp homology) domain 1 (SPRED1). Obtaining a clinical and molecular diagnosis of NF1 or LS can be challenging due to the phenotypic diversity, the size and complexity of the NF1 and SPRED1 loci, and uncertainty over the effects of some NF1 and SPRED1 variants on pre-mRNA splicing and/or protein expression and function. To improve NF1 and SPRED1 variant classification and establish pathogenicity for NF1 and SPRED1 variants identified in individuals with NF1 or LS, we analyzed patient RNA by RT-PCR and performed in vitro exon trap experiments and estimated NF and SPRED1 protein expression, RAS GAP activity, and interaction. We obtained evidence to support pathogenicity according to American College of Medical Genetics guidelines for 73/114 variants tested, demonstrating the utility of functional approaches for NF1 and SPRED1 variant classification and NF and LS diagnostics.

Neuropsychiatric Manifestations, Reduced Self-Esteem and Poor Quality of Life in Children and Adolescents with Neurofibromatosis Type 1 (NF1): The Impact of Symptom Visibility and Bullying Behavior.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, associated with neurocutaneous manifestations and neuropsychiatric manifestations. The present study explored the prevalence of bullying/cyberbullying behaviors and victimization behaviors in a cohort of children and adolescents with NF1. Possible gender differences and predictors of psychological symptoms, quality of life (QoL), and self-esteem were also examined. Thirty-eight school-aged participants with NF1 completed a psychological evaluation designed to assess anxiety and depression symptomatology, QoL, self-esteem, and the prevalence and extent of bullying/cyberbullying and victimization behaviors. We found that our participants frequently reported victimization behaviors rather than bullying/cyberbullying ones. Moreover, participants complained of depressive and anxiety symptomatology together with reduced self-esteem, and low psychosocial quality of life, with females reporting more severe performances than males. Furthermore, we found that reduced self-esteem was associated with more visibility of the NF1 symptoms, and victimization behaviors were found to mediate the relationship between anxiety and psychosocial QoL. Our findings indicated the presence of a maladaptive loop in children and adolescents with NF1 patients characterized by psychological symptoms, unfavorable self-perception, low self-esteem, and psychosocial difficulties that might be worsened by experiencing victimization behaviors. These results suggest the need to use a multidisciplinary approach in the diagnosis and treatment of NF1.

Relative size of fungiform papillae in patients with neurofibromatosis Type 1

ObjectiveTo explore possible manifestations of neurofibromatosis on the tongue, especially, enlarged papillae fungiformes. According to the literature, enlarged fungiform papillae of the tongue are a very common oral finding in patients with Neurofibromatosis Type 1 (NF1). Materials and MethodsFirstly, photos of 18 NF1 patients’ tongues, taken at different times were compared to rule of possible fluctuating papillae size. Secondly, 60 photos of 60 patients with NF1 were age/sex matched, blinded and compared to 60 photos of 60 healthy patients. Three independent medical doctors rated the photos in regard of the fungiform papillae as smaller/same/larger at two different times. The inter- and intraindividual results were compared.Thirdly, fungiform papillae of 11 NF1 patients were quantitatively measured using the Denver protocol. ResultsThe fungiform papillae showed a stable size. The comparison of the healthy individuals to the NF1 patients suggests that the larger papillae are significantly more frequent in NF1 patients than in age- and gender-matched non-NF1 individuals. The agreement between two ratings of each of the 3 raters at different time points was two moderate and one substantial, the agreement among raters was only fair, since the Fleiss’ Kappa value of all 6 ratings was 0.38. ConclusionAlthough this study confirms that the evaluation of the size of the fungiform papillae by visual inspection only is very subjective, the fungiform papillae in NF1 patients do seem to be enlarged at a statistically significant level. Nonetheless the statistical difference is not distinctive enough to establish this as a diagnostic tool in diagnosing NF1. Clinical RelevanceFacilitating the diagnosis of NF1 is an important factor in finding the correct treatment for these patients. A clinical inspection of the tongue is a simple and non-invasive procedure. This paper addresses the question if an inspection of the tongue, especially the fungiform papillae is a reliable indicator for the diagnosis of NF1.

Using a semi-automated approach to quantify Unidentified Bright Objects in Neurofibromatosis type 1 and linkages to cognitive and academic outcomes

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous syndrome that affects multiple organ systems resulting in widespread symptoms, including cognitive deficits. In addition to the criteria required for an NF1 diagnosis, approximately 70% of children with NF1 present with Unidentified Bright Objects (UBOs) or Focal Areas of Signal Intensity, which are hyperintense bright spots seen on T2-weighted magnetic resonance images and seen more prominently on FLAIR magnetic resonance images (Sabol et al., 2011). Current findings relating the presence/absence, quantities, sizes, and locations of these bright spots to cognitive abilities are mixed. To contribute to and hopefully disentangle some of these mixed findings, we explored potential relationships between metrics related to UBOs and cognitive abilities in a sample of 28 children and adolescents with NF1 (M=12.52 years; SD=3.18 years; 16 male). We used the Lesion Segmentation Tool (LST) to automatically detect and segment the UBOs. The LST was able to qualitatively and quantitatively reliably detect UBOs in images of children with NF1. Using these automatically detected and segmented lesions, we found that while controlling for age, biological sex, perceptual IQ, study, and scanner, “total UBO volume”, defined as the sum of all the voxels representing all of the UBOs for each participant, helped explain differences in word reading, phonological awareness, and visuospatial skills. These findings contribute to the emerging NF1 literature and help parse the specific deficits that children with NF1 have, to then help improve the efficacy of reading interventions for children with NF1.

Piebaldism with Neurofibromatosis-1 with Skeletal Anomalies in Two Successive Generations

Piebaldism is a rare autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair due to mutations of the c-KIT gene on chromosome 4q12. Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder. We present a case report of three siblings with piebaldism with neurofibromatosis-1. They presented with depigmented lesions over the abdomen and knees since birth. Two of them had white forelock of hair. The oldest sibling had gait abnormality, scoliosis, and reported repigmentation over the forehead lesion. Along with that, multiple café-au-lait macules were present in all the three siblings of size more than 5 mm in diameter and more than 6 in number. Their father had a history of similar depigmented macules over both shins and he also developed freckles over the axilla, palms, and feet. Diagnosis of piebaldism and NF1 was based on clinical features, and the National Institute of Health Consensus Conference in 1987 has given seven diagnostic criteria.

Childhood-Onset Refractory Hypertension Results from Neurofibromatosis Type 1 Caused by a Splicing NF1 Mutation

Introduction: Neurofibromatosis type 1 (NF-1) is caused by mutations in the NF1 gene that encodes neurofibromin, a negative regulator of RAS proto-oncogene. Approximately one-third of the reported pathogenic mutations in NF1 are splicing mutations, but most consequences are unclear. The objective of this study was to identify the pathogenicity of splicing mutation in a Chinese family with NF-1 and determine the effects of the pre-mRNA splicing mutation by in vitro functional analysis. Methods: Next-generation sequencing was used to screen candidate mutations. We performed a minigene splicing assay to determine the effect of the splicing mutation on NF1 expression, and three-dimensional structure models of neurofibromin were generated using SWISS-MODEL and PROCHECK methods, respectively. Results: A pathogenic splicing mutation c.479+1G>C in NF1 was found in the proband characterized by childhood-onset refractory hypertension. In vitro analysis demonstrated that c.479+1G>C mutation caused the skipping of exon 4, leading to a glutamine-to-valine substitution at position 97 in neurofibromin and an open reading frame shift terminating at codon 108. Protein modeling showed that several major domains were missing in the truncated neurofibromin protein. Conclusion: The splicing mutation c.479+1G>C identified in a Chinese patient with NF-1 and childhood-onset refractory hypertension caused the skipping of exon 4 and a truncated protein. Our findings offer new evidence for the molecular diagnosis of NF-1.

Neurosurgical Presentations of Neurofibromatosis Type 1: Our Experience in a Regional Neurosurgical Centre, Sokoto, Nigeria

Objective: The objective of this paper was to highlight various neurosurgical presentations of patients with neurofibromatosis type 1 seen in our center. Design: This is retrospective analysis of all cases of neurofibromatosis type 1 seen in our neurosurgical center over five- year period. Data was extracted from case files retrieved from medical records department of the hospital. Biodemographic characteristics, clinical presentations, neuroimaging findings and treatment offered were noted. Setting: A single center report conducted at department of neurosurgery, regional neurosurgical center, Usmanu Danfodiyo university teaching Hospital Sokoto. Participants: All patients presenting to neurosurgery department with a diagnosis of neurofibromatosis type 1 over five-year period. Interventions: Among the patients seen, three had surgical intervention for disfiguring plexiform neurofibroma. While the remaining two patients refused any form of surgery. Cosmesis was main study outcome which was satisfactory to both the surgeons and the patients. Results: We found a total of five cases managed over the study period. Three males and two females, the youngest was 2 weeks old while the oldest was a 22-year-old man. Three patients had major cranial lesions while two presented with spinal/paraspinal lesions. Also, only three patients met NIH criteria for the diagnosis of NF-1, two presented with only plexiform neurofibromatosis. Two patients declined any form of surgical intervention. Cosmesis was the only reason for presenting to the hospital. Postoperative outcome was good for the three patients that accepted surgery. Conclusion: Neurofibromatosis type 1 occurs at a rate of one case per year in our setting. Various cranial and spinal/paraspinal manifestations were observed.

Genetic analysis of two children with sporadic neurofibromatosis type 1 complicated with nephrotic syndrome

To explore the genetic basis for two children with sporadic neurofibromatosis type 1 (NF1) complicated with nephrotic syndrome (NS). Clinical data of the children were collected. Both children were subjected to high-throughput sequencing, and candidate variants were verified by Sanger sequencing. Both children had café-au-lait macules, subaxillary freckle and Lisch nodules. Child 1 also had congenital tibiofibular pseudarthrosis on the left side. Genetic testing revealed that child 1 has harbored a heterozygous c.844C>T variant in the exon 8 of the NF1 gene, whilst child 2 has harbored a heterozygous c.1246C>T variant in the exon 11 of the NF1 gene. Both children were diagnosed with NF1 and have developed pronounced proteinuria, hypoalbuminemia, hypercholesterolemia and pitting edema at the ages of 3 and 10, respectively. Renal biopsy of child 2 has revealed minimal change nephropathy, and the diagnosis of nephrotic syndrome was established. Child 1 was treated with glucocorticoid, and child 2 was treated with glucocorticoid in combination with mycophenolate mofetil. The NS was relieved with no recurrence during 1 year's follow-up. NF1 combined with NS is rare in the clinical settings. The prognosis of children with NF1 combined with minimal change nephropathy is relatively good. Detection of NF1 gene variant can facilitate early identification and diagnosis of NF1.

Retinal vascular abnormalities in children with neurofibromatosis type 1

AbstractPurpose: Retinal vascular abnormalities (RVA) have been recently described in patients with neurofibromatosis type 1 (NF1) as vascular tortuosity, best visible on infrared imaging. This study assessed clinical RVA's characteristics in a large series of children with NF1.Methods: This retrospective observational study was conducted in children (0–18 years old) with an NF1 diagnosis. Using near infrared imaging, RVAs were classified according to the nature of vessels involvement and their degree of tortuosity.Results: Retinal imaging from 140 children, with a median age of 8.8 [1.5–18] years, were included; 52 (37.1%) patients (81 eyes) exhibited RVAs. These RVAs comprised 96% (50/52) of simple vascular tortuosity and 17% (9/52) of cork‐screw pattern. Cork‐screw pattern involved only small veins, while simple vascular tortuosity could affect both arteries and veins. No statistically significant age correlation was observed, but evolution of RVAs from simple vascular tortuosity to cork‐screw pattern was observed in 5 cases.Conclusions: Retinal vascular abnormalities occurred in 37.1% of children with NF1. These abnormalities may result from NF1 promoting localized tortuosity in both small arteries and veins, while only small second or tertiary order venules evolve to highly tortuous pattern.

Decision Making for Active Surveillance in Vestibular Schwannoma.

To describe the experiences of patients who elected for the active surveillance treatment option for their vestibular schwannoma (VS). Twenty-two patients participated in semistructured patient interviews. Interviews were conducted between March and April 2021 via telephone with audio recordings and notes taken during each interview. Adults diagnosed with a VS and at any point after their diagnosis underwent a period of active surveillance were recruited based on the diagnosis made by MRI. Patients were excluded if they chose to undergo treatment immediately, had a diagnosis of neurofibromatosis type 2, or if they had a confirmed alternative diagnosis. This intervention was a qualitative interview to assess patient experiences with their VS treatment decision. Identifying abstract categories that represent many of the stories told by the participants that produces a theory grounded in the data with explanatory power. Factors that influenced patients' treatment decisions were perceived physician bias, selfeducation, and personal accounts of VS patients through support groups, and side effects/complications of the various treatment options. Patients who opted for active surveillance as a treatment option reported high satisfaction with their decision and greater confidence in future treatments that would be necessary based on tumor growth. Future work should be done to increase shared decision making between the physician and patient to arrive at a treatment plan that aligns with their goals of care as well as potentially reducing overtreatment of VS.

Maxillofacial Radiology 203

19-year-old male patient, known with a diagnosis of neurofibromatosis type 1, presented with a plexiform neurofibroma involving the left orbit, zygoma, temporal, and parotid regions. The patient reported a history of left eye enucleation 7-years-ago. What are the pertinent radiologic findings? (Figs.1 and 2)

Novel, heterozygous, pathogenic variant (c.4272delA: p.I1426Ffs*2) for the NF1 gene in a large Chinese family with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant with haploinsufficient, and multisystemic disorder including patches of skin Café-au-lait spots, Lisch nodules in the iris, and tumors in the peripheral nervous systems or fibromatous skin. Blood samples were collected and DNA was extracted from a large Chinese pedigree suffering from NF1 disease with three spontaneous abortions or death for proband. Analysis for whole exome sequencing (WES), Sanger sequencing, and co-segregation was carried out. Prenatal gene diagnosis was also carried out in amniotic fluid DNA. The expression of NF1 was conducted by bioinformatics. A large Chinese pedigree with NF1 was recruited and a novel, heterozygous, variant (c.4272delA: p.I1426Ffs*2) for the NF1 gene in the proband was identified. This variant of NF1 produced a truncated protein that losses half of NF1 protein at the C-terminus including the CRAL-TRIO lipid-binding domain, NLS, and a small portion of Ras-GAP domain, thus leading to pathogenicity (ACMG criteria: PVS1 + PM2). NF1 expressions in different human tissues showed low tissue specificity, which may affect multiple organs presenting different phenotypes. Moreover, prenatal gene diagnosis for NF1 showed both alleles as wild types in the fetus of the proband. We thus successfully identified a novel, pathogenic, heterozygous variant (c.4272delA:p.I1426Ffs*2) in the NF1 gene of NF1 disorder, expanding the NF1 mutation spectrum, that will help elucidate the molecular pathogenesis of NF1 disease and to contribute to the NF1 diagnosis, genetic counseling, clinical management in this large Chinese family.

NIMG-15. INTEGRATED RADIOGRAPHIC AND PATHOLOGICAL ANALYSIS OF MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNSTS) REVEALS IMAGING CORRELATES OF MOLECULAR ALTERATIONS AND CLINICAL OUTCOME

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in patients with neurofibromatosis type 1 (NF-1) yet non-invasive diagnosis and risk stratification of NF-1-associated peripheral nerve tumors remains challenging. Moreover, the relationship between radiographic features and pathologic measures such as mitotic index and necrosis, or molecular markers of malignant transformation such as H3K27 trimethylation and Schwann cell marker (S100B, SOX10) expression remain unknown. Here, we integrate positron emission tomography (PET) (n=32 studies from 18 patients) and magnetic resonance imaging (MRI) (n=20 studies from 20 patients) with immunohistochemical analysis and clinical follow-up in a total of 20 patients with pathologically confirmed MPNST diagnosis. The median age was 33 years (range 5-74 years), n = 11 were male (55%) and n=13 (65%) harbored a clinical diagnosis of NF-1. Anatomically, n=6 (30%) tumors arose near the spine, n=5 (25%) arose in the extremities, and n=4 (20%) arose in the sacrum. By PET, the average preoperative SUVmax was 8.53 with a trend toward increased SUVmax in Ki-67 high tumors (SUVmax 10.58 vs. 6.47, p=0.08). No significant differences in SUVmax based on H3K27 trimethylation, SOX10, or S100B expression was noted. The appearance of cystic necrosis by MRI was significantly associated with H3K27 trimethylation loss (Chi-square p=0.04) with a trend toward increased KI-67 labeling (43% vs. 24%, p = 0.07), suggesting cystic necrosis identifies aggressive lesions. No other features were correlated with H3K27 trimethylation status or Ki-67 labeling index. With regard to clinical outcome, dichotomized SUVmax identified patient subgroups with significant differences in overall survival (OS), with high SUVmax tumors demonstrating improved survival (median OS: 250 months vs. 60 months, log-rank test p=0.02). Our data support a relationship between radiographic features, histopathologic characteristics and clinical outcomes. Future work will include longitudinal analysis, validation in larger, multi-institutional cohorts and incorporation of radiomic approaches.

Metastatic proximal-type epithelioid sarcoma presenting as a chest lesion with a pathological fracture of the humeral neck

Introduction: Proximal-type epithelioid sarcoma is a rare soft tissue neoplasm which occurs mostly in young males and is much rarer than classic distal sub type. A young male, with a known diagnosis of neurofibromatosis type 1 (NF1) presenting with metastatic proximal-type epithelioid sarcoma is reported. Case Report: A 30-year-old male with known NF1, hypothyroidism, epilepsy, presented with a right shoulder pain of two weeks duration. Plain radiographs revealed an expansile lytic lesion, an aggressive periosteal reaction in right humeral head with an underlying pathological fracture. A well-defined extrapulmonary mass with a lobulated margin in upper zone of right hemithorax with inferior rib erosion of 3rd rib and the 3rd intercostal space widening were also observed. Contrast-enhanced computed tomography (CECT) chest and abdomen confirmed peripherally located poorly enhancing soft tissue mass with lobulated margins arising from posterior chest wall along with a subdiaphragmatic deposit. Multiple lytic lesions in right head of humerus with an underlying pathological fracture of surgical neck, T2, T6, and L3 vertebral bodies, and pelvic bones were observed too. Diagnosis of malignant peripheral nerve sheath tumor with metastases was made and ultrasound-guided biopsy of chest wall lesion was performed. Histology and immunohistochemistry (IHC) revealed a proximal type epithelioid sarcoma. The patient was managed with palliative surgery and oncological follow-up. Conclusion: Presentation of proximal-type epithelioid sarcoma with disseminated metastases in a patient with NF1 masquerading malignant peripheral nerve sheath tumor (MPNST) and the challenges of diagnosis on clinical, radiological, and histopathology as well as IHC perspectives of this rare disease entity is highlighted.

Traumatic Brain Injury, Bulging Eyeball, and Skin Lumps

A 43-year-old man was admitted to the emergency department for motor vehicle collision. First clinical impression was traumatic injury of the right eye with bare light perception. A physical examination revealed multiple nodular skin lesions on the head and neck. Head magnetic resonance imaging and computed tomography scans showed intracerebral hemorrhage, trans-orbital brain herniation, and right sphenoid wing dysplasia. A diagnosis of neurofibromatosis type 1 was made. Sphenoid wing dysplasia (also known as bare orbit sign) in neurofibromatosis type 1 was a contributing factor to the trans-orbital herniation, but also helped reduce intracranial pressure after traumatic brain injury in this rare case. Mannitol was administered, and no neurosurgical intervention was needed for traumatic brain injury. Canthorrhaphy of the right eye was performed to preserve patient's right eyeball. At 1-month follow-up, patient's right eyeball was preserved, and vision improved as well.

Hallazgos cutáneos no considerados criterios diagnósticos de la NF1. Estudio de casos y controles

BackgroundThe diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. Patients and methodsCase–control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. ResultsThe prevalence of nevus anemicus (NA) (P<.001) and juvenile xanthogranulomas (JXG) (P<.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% (confidence interval): 95.4–99.96%] and a positive predictive value (PPV) of 98.80% [92.54–99.94%] were estimated for NA and a specificity of 99.27% [95.4–99.96%] and a PPV of 92.86% [64.17–99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (P=.025) and in relation to generalized itching with no other cause (P<.001). ConclusionsNA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.